Wntless functions in mature osteoblasts to regulate bone mass

• DOI: 10.1073/pnas.1120407109
• Publication Date: 2012-06-29T00:19:10Z
• Authors: Zhendong Zhong; Cassandra R. Zyls...; Cassie A. Schumacher; Jacob J. Baker; April C. Carpenter; Sujata Rao; Wei Yao; Min Guan; Jill A. Helms; Nancy E. Lane; Richard A. Lang; Bart O. Williams
• Keywords: Conditional gene knockout

Recent genome-wide association studies of individuals Asian and European descent have found that SNPs located within the genomic region (1p31.3) encoding Wntless (Wls)/Gpr177 protein are associated significantly with reduced bone mineral density. Wls / Gpr177 is a newly identified chaperone specifically escorts Wnt ligands for secretion. Given strong functional between signaling pathways development homeostasis, we generated osteoblast-specific Wls-deficient ( Ocn-Cre;Wls-flox ) mice. Homozygous conditional knockout animals were born at normal Mendelian frequency. Whole-body dual-energy X-ray absorptiometry scanning revealed bone-mass accrual was inhibited in homozygotes as early 20 d age. These had spontaneous fractures high frequency premature lethality around 2 mo Microcomputed tomography analysis histomorphometric data dramatic reduction both trabecular cortical mass homozygous mutants. Bone formation severely impaired, but no obvious phenotypic change observed mice heterozygous deletion. In vitro showed -deficient osteoblasts defect differentiation mineralization, significant reductions expression key osteoblast regulators. summary, these results reveal surprising crucial role osteoblast-secreted accrual.